Have Faster FDA Drug Approvals Caused More Safety Problems?

Has a law designed to speed drug approvals resulted in excessive safety issues?

A new study finds that after the Prescription Drug User Fee Act was passed in 1992 – in which drug makers agreed to pay fees to help fund the FDA and the agency agreed to accelerate approvals – the number of safety warnings and product withdrawals was higher than before the law was passed.

Specifically, after the law passed, the rate of Black Box warnings, the most severe type of warning about a safety issue, and withdrawals was 26.7 out of 100 drugs approved versus 21.2 prior to passage.

For all drugs approved between 1975 and 2009, there was a one-in-three chance that, after the law passed, a medicine had received a Black Box warning or a drug was withdrawn from the market, according to the study, which was published in Health Affairs.

Put another way, for every 100 drugs arriving in pharmacies, there were 34 withdrawals or Black Box warnings during that time period. Half of the new warnings appeared within 12 years after a drug was launched and half of the withdrawals occurred within five years.

Earlier studies that explored this topic offered conflicting findings, but examined drug approvals for only a few years following passage of the law. So the researchers examined approvals over a 35-year period, but none since 2010, when their study began. They relied on the most recent warning data available. The latest study examined 748 new drugs that were approved between 1975 and 2009.

The study purports to be the most extensive to examine this issue since the law was passed. At the time, there was considerable debate about the ability of the FDA to approve drugs more quickly. The pharmaceutical industry complained the agency took too long and was making an expensive process still more costly. And patient groups argued that faster approvals could save or improve lives.

Conversely, consumer advocates worried that FDA independence may be compromised by industry payments, which could theoretically influence approval decisions that may also lead to safety issues. Nonetheless, the law – known as PDUFA – was not only passed in 1992, but was renewed several times since then.

The study authors, however, contend that their findings illustrate how those concerns hold validity, even though they acknowledge that they could not determine that the law actually was the reason for increased safety problems.

“The FDA is under constant pressure to rush new drugs through the pipeline to approval,” says study co-author Cassie Frank, a physician at Cambridge Health Alliance and an instructor in medicine at Harvard Medical School, in a statement.

“In its hurry, the FDA is apparently failing to distinguish useful drugs from toxic ones, and more dangerous drugs are slipping through. By the time many drugs receive serious safety warnings, millions of Americans have already been exposed to their side effects, which can sometimes be fatal.”

But if the authors are uncertain why the number of warnings and withdrawals increased, what might have been the cause? They speculate that approvals imposed by PDUFA deadlines may have rushed the FDA. They also cite a theory that faster approvals may have compromised clinical trial evidence.

In any event, the researchers says their findings suggest a need for reforms to reduce patient exposure to unsafe drugs, such as a statement or symbol in the labeling, medication guides for patients, and marketing materials indicating that a drug was approved only recently. They also advocate for a ban on direct-to-consumer advertising within the first several years after an approval.

In response, the pharmaceutical industry trade group, the Pharmaceutical Research & Manufacturers of America for comment, sent us this note:

“Prior to 1992, the drug review process was unpredictable, lagging behind other countries and stalling patient access to critical new medicines. Providing the FDA with stable, consistent funding, PDUFA revolutionized the process and strengthened the agency’s high safety and efficacy standards.

Since its enactment in 1992, PDUFA has sped up patient access to over 1,500 new medicines, including treatments combating some of our nation’s most deadly diseases. By injecting greater consistency, transparency, and predictability into the drug review process, PDUFA has played a crucial role in improving public health.”

We asked the FDA for comment and will pass along any response that we receive.

[UPDATE: The FDA has now responded by writing to say the agency "has just received the study and we are currently reviewing it."

And the agency adds this: "PDUFA has enhanced pre-market review and created a modern post-market drug safety system that follows products across their full life cycle. Specifically, PDUFA provides FDA revenue to hire additional reviewers and support staff and upgrade its information technology systems to maximize the efficiency of the application review process for new drugs and biological products without compromising FDA’s high standards for approval.

"Additionally, PDUFA funding has helped the FDA modernize and transform the post-market drug safety surveillance system. It has helped ensure the safety of drugs after they are approved for as long as they remain on the market and have increased FDA's drug safety surveillance capacity. FDA has been able to adopt new scientific approaches and improve the utility of existing tools for the detection and prevention of adverse events, including obtaining access to the best available databases to better analyze drug safety signals."]

Comments (5 of 8)

Dr. Oldham is on point with his comment. Discussions on risk should only be presented in the context of their risk:benefit ratio. If a product comes to market with a boxed warning, how do we balance the medical need with the risk (e.g. death from spinal muscular atrophy in a 1 year old vs. severely stunted growth). I applaud innovation and a more efficient development process - these new designations and speedier development times are finally bringing therapies to pediatric rare diseases, where they have never been previously considered. Relying only on what has been in the market for years doesn't always meet our patient's needs.

7:57 am August 6, 2014

also a pharma guy wrote:

The first comment says all. If a faster drug approval saves 20 lives and improves thousands, how does that compare with the ADR profile? It's not a pleasant calculation, but if the drug saved 20 and killed one there is a strong argument that the faster approval was beneficial. It won't stop the lawsuit, and the plaintiff will probably win, but aside from making the drug more expensive as a result society will have benefitted.

What is also not mentioned is the political aspect of black box warnings. Post Vioxx FDA has been much shyer about approving "me too" drugs. There is a clear perception both within Congress that FDA dropped the ball on that one. While I don't have the numbers at hand, I would be shocked if the percentage of black box warnings was not higher from 2004-2014 than from 1994-2004.

Nobody wants to market a dangerous drug, and nobody wants a black box warning, but as pharma guy's linked article shows in the case of the beta blockers, they are not always applied consistently. While I do not question FDA's desire to ensure a safe drug supply, I doubt that in every case the only considerations are scientific.

2:45 pm August 5, 2014

pharma guy wrote:

Nice to hear from Dr Leber, one of the smartest guys that ever worked for FDA. Actually the raw number of boxed warnings is fairly inconsequential. What's more important is the survival time of a drug on the market until it has acquired a black box and/or is withdrawn. Below is a good analysis by Dr Sidney Wolfe, who studied this phenomenon over a 25 year period from 1975-2000. The paper shows the Kaplan-Meier curve for the probability of a newly approved drug to acquire a boxed warning or be withdrawn post approval. Since a similar time period post PDUFA has elapsed it would be interesting to repeat the K-M analysis, comparing pre PDUFA (1975-1992) to post PDUFA (1992 to present) and compare the curves.

When diiscussing the value / risk of speeding up approvals 20+ years ago, the agreement was - get appoved in 7 years or in 5 years - 7 years allows time for more side effects to show up. And they will simply because there's more time.

1:21 pm August 5, 2014

Paul Leber wrote:

Paolo Pignatelli nailed it. The fact that night follows day does not mean that day is the cause of night. Moreover, beyond the fallacy of the inferential method employed by the article's author, the outcome metric chosen, the combined numbers of black boxes and product withdrawals, is neither a valid nor reliable measure of the quality of the premarket reveiw process upon which the agency relies to approve new drugs for marketing.

About Pharmalot

Pharmalot explores the fast-moving, complicated world that develops and markets medicines – and the drug makers that are attempting to replenish their pipelines while grappling with pricing and regulatory dictates, among many other challenges. Writer Ed Silverman has covered the pharmaceutical industry for nearly two decades and has closely followed the many hurdles facing drug companies as they move ideas from the laboratory to the medicine chest. He started Pharmalot while at The Star-Ledger of New Jersey and previously worked at New York Newsday and Investor’s Business Daily. Email Ed Silverman at ed.silverman@wsj.com, and follow him on Twitter @Pharmalot.